Rapamycin 42-ester with 2,2-bis(hydroxymethyl) propionic acid (CCI-779) is an ester derivative of rapamycin which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. The preparation and use of hydroxyesters of rapamycin, including CCI-779, have been described in U.S. Pat. Nos.: 5,362,718 and 6,277,983.
Esterification of rapamycin at the 42-position was previously conducted by directly reacting rapamycin with acylating agents. However, as rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoacylated product still posed a difficult challenge. Currently, a regioselective process for the preparation of CCI-779 involves at least five steps (U.S. Pat. No. 6,277,983, International Patent Publication No. WO 01/23395). First, rapamycin is treated with a silylation agent to form rapamycin 31,42-bis-silyl ether, and then the 42-silyl ether protection group is selectively removed to provide rapamycin 42-OH-31-silyl ether. This freed 42-OH was then acylated with 2,4,6-trichlorobenzyl mixed anhydride of 2,2,5-trimethyl[1,3-dioxane]-5-carboxylic acid and two subsequent deprotection steps furnish the desired CCI-779.
CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S. CCI-779 has been demonstrated to be effective in multiple applications, including inhibition of central nervous system cancer, leukemia, breast cancer, prostate cancer, melanoma, gliomas, and glioblastoma.
What are needed are more efficient methods for regiospecific production of CCI-779, and analogs thereof.